tbuckley/cabot-search huggingface dataset:
Trial in progress: A phase 2/3 randomized, controlled study of CTX-009 in combination with paclitaxel versus paclitaxel alone in adult patients with unresectable advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen.
Authors: Marilyn Fontaine, Sarah Pilgrim, Thomas Schuetz
Journal: Journal of Clinical Oncology (2023)

TPS640 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Presently, there is no consensus second-line therapy for patients with Biliary Tract Cancer (BTC) in whom first-line therapy has failed. In a Phase 1b study of CTX-009 in combination with paclitaxel, there were 4 patients with cholangiocarcinoma enrolled, and 2 of these 4 patients (both received CTX-009 at 10mg/kg + paclitaxel) had confirmed PRs with declines of 41.4% and 61.6% in their linear tumor burden from the baseline. Both of these patients had multiple prior therapies, and were on study for more than a year, with durable responses for more than 9 months each. Based on that observation, an adaptive Phase 2 cohort was added to the Phase 1b Study. There are currently 9 confirmed PRs among 24 patients treated for a 37.5% overall response rate in the ongoing Phase 2 Study of CTX-009 in combination with paclitaxel in patients with BTC treated in the second- or third-line setting. While there is anecdotal data suggesting that taxanes may have activity in BTC, the contribution of CTX-009 needs to be confirmed in a randomized study. Methods: CTX-009 is being evaluated in an open-label, randomized, controlled study in patients with previously treated, advanced or metastatic BTC. 120 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include sex, presence of disease inside the liver only (intrahepatic cholangiocarcinoma) vs. outside the liver (all extrahepatic BTC or metastatic disease), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. The study is currently activating sites with first patient in expected to be enrolled in 2022. Clinical trial information: NCT05506943 .
Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic CRC: Analysis of patients treated within the PanaMa trial (AIO KRK 0212).
Authors: Meinolf Karthaus, Greta Sommerhäuser, Annika Kurreck, Alexander Beck, Uli Fehrenbach, Stefan Fruehauf, Ullrich Graeven, Lothar Müller, Alexander Koenig, Ludwig Fischer von Weikersthal, Eray Goekkurt, Siegfried Haas, Arndt Stahler, Volker Heinemann, Swantje Held, Annabel Helga Sophie Alig, Stefan Kasper, Sebastian Stintzing, Tanja Trarbach, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2023)

127 Background: Despite molecular selection, patients with RAS wildtype mCRC represent a heterogeneous population, including different metastatic patterns and number of organs involved. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. Methods: The study population was stratified according to number of organs involved and also to different patterns including liver metastases alone or in combination with additional organs. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints (i.e. progression-free survival (PFS) and overall survival (OS) of maintenance therapy) in the aforementioned populations. Results: Of 248 patients (pts) receiving maintenance therapy, 133 pts had a one-metastatic site disease (53.6%). Of those, 102 pts had liver-only metastases. Furthermore, liver metastases plus one additional involved organ was observed in 61/248 patients (24.6%), and liver metastases plus two or more organs in 40/248 patients (16.1%). In general, one organ disease was associated with favourable PFS of maintenance therapy compared to patients with ≥2 organs involved (HR 0.68, 95% CI 0.52–0.88; P = 0.004). A predictive impact of disease spread in terms of pmab-containing maintenance therapy was present for the PFS of maintenance therapy in patients with ≥ 2 organ disease (HR 0.58, 95% CI 0.39–0.86; P = 0.006) unlike in patients with only one-organ disease (HR 0.83, 95% CI, 0.57-1.21; P = 0.332) and also specifically in patients with a 2-organ disease including the liver (HR 0.57, 95% CI 0.33–0.99; P = 0.046). Conclusions: Consistent with previous reports, organ spread has prognostic impact in mCRC. The efficacy of more intensive maintenance therapy (including pmab and 5-FU/FA) is predominantly seen in patients with more than one organ involved in the metastatic spread, while less striking effects were seen in patients with only one organ disease. These data may support clinical decisions when EGFR-based maintenance therapy is considered. Clinical trial information: NCT01991873 .
Utility of AST to platelet ratio index (APRI) score in predicting post-surgical outcomes in patients with cholangiocarcinoma.
Authors: Faaiq Aslam, Tristan Loveday, Pedro Luiz Serrano Uson Junior, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2023)

502 Background: Cholangiocarcinoma (CCA) is an epithelial malignancy of the intrahepatic or extrahepatic biliary tree, primarily driven by chronic inflammation and fibrosis. Given fibrosis has shown to correlate with malignancy and the aminotransferase-platelet ratio index (APRI) score, a marker for hepatic fibrosis, has shown to be useful in prognosticating hepatocellular carcinoma, this study aimed to assess the utility of APRI score in prognosticating post-surgical outcomes in CCA patients. Methods: 152 CCA patients at the Mayo Clinic that underwent surgical resection were retrospectively analyzed. Statistical analyses were then conducted to determine the relationship between APRI score and demographic factors, laboratory values (CA19-9, albumin, bilirubin, INR, alkaline Phosphatase, ALT, AST, and platelet count), pathology features, and outcome data. Results: When looking at demographic factors, no relationship between APRI score and age (r = -0.19, p = 0.02), sex (2-sample t-test p = 0.16) and race (ANOVA p = 0.81) were identified. There was a negative correlation between APRI score and albumin (m = -0.35, r = -0.35, p &lt; 0.01) and a positive correlation with bilirubin (m = 0.13, r = 0.23, p = 0.01) and ALT (m = 0.01, r = 0.47, p &lt; 0.01). No correlation between the other laboratory values analyzed was identified. Similarly, there was no relationship between APRI score and pathology features (tumor grade t-test p = 0.41, N Stage ANOVA p = 0.94, Vascular Invasion t-test p = 0.59, and Perineural invasion t-test p = 0.14), except for T3 stage which had a higher APRI score compared to T1, T2, and T4 (ANOVA p = 0.01). Likewise, APRI also did not correlate with post-surgical outcomes like recurrence (t-test p = 0.22) and mortality (t-test p = 0.39). Conclusions: In summary, despite being driven by chronic inflammation, APRI score, a marker for hepatic inflammation and a surrogate for liver fibrosis, did not serve as a reliable prognostication tool of post-surgical outcomes in CCA patients. These data suggest that although chronic inflammation is thought to be one of the primary drivers of disease, the role of other factors such as genetic and cellular signaling abnormalities may play a more prominent role in patients with CCA. In conclusion, APRI score did not serve as a useful prognostication tool in surgically resected CCA patients. Future studies should focus on other prognostic factors such as genomic and transcriptomic biomarkers in CCA.
Preoperative camrelizumab combined with chemotherapy for borderline resectable esophageal squamous cell carcinoma (BRES-1): A single-arm, open-label, phase II study.
Authors: Hang Yang, Guoqing Zhang, Xiangnan Li, Jia Jiao, Yanan Guo, Yan Zhang, Zhichao Hou, Qi Huang, Jia Zhao, Jindong Li
Journal: Journal of Clinical Oncology (2023)

360 Background: Patients with borderline resectable esophageal squamous cell carcinoma have poor prognosis and poor response to first-line therapy. The BRES-1 study aimed to assess the efficacy and safety of camrelizumab combined with chemotherapy in patients with borderline resectable esophageal squamous cell carcinoma. Methods: This single-center, single-arm prospective phase II clinical trial will enroll 30 patients with borderline resectable esophageal squamous cell carcinoma. The 30 enrolled patients will receive preoperative camrelizumab with chemotherapy regardless of programmed death ligand-1 status. Preoperative therapies will include camrelizumab, nab-paclitaxel and cisplatin. Surgery will be performed 3-4 weeks after the completion of the preoperative neoadjuvant therapy. Three weeks after surgery, two periods of maintenance therapy will be continued with camrelizumab combined with chemotherapy. Then, maintenance treatment will be continued with camrelizumab up to one year. Primary endpoints included pathologic complete response (pCR), major pathological response (MPR). Results: As of September 15, 2022, 19 patients who met the criteria were enrolled (63% males, median age 67), neoadjuvant therapy was completed in 18 patients and ongoing in 1 patients. Among the 19 patients, 11 patients were resected and all patients underwent an R0 resection. 5 patients (45%) reached major pathologic response, 3 patients (27%) reached pathologic complete response, 8 patients (8/11, 73%) with complete regression (TRG 1) or near-complete regression (TRG 2). No grade 3-4 immunotherapy related AEs were observed, no surgery related mortality. The most common treatment-related AEs were leukopenia (18/19, 95%), lymphopenia (18/19, 95%) and anaemia (15/19, 79%). Conclusions: Camrelizumab with chemotherapy for borderline resectable esophageal squamous cell carcinoma has shown good conversion rates. Its efficacy and safety will be further investigated in later trials. Clinical trial identification: ChiCTR2200056728.
Bevacizumab in first-line therapy in lung metastases of colorectal cancer: An ARCAD pooled analysis.
Authors: Einat S Shmueli, Morteza Raeisi, Benoist Chibaudel, Herbert Hurwitz, Leonard B. Saltz, Fairooz F. Kabbinavar, Niall C. Tebbutt, Axel Grothey, Richard Adams, John Raymond Zalcberg, Takayuki Yoshino, Jean-Baptiste Bachet, Romain Cohen, Lama Sharara, Thierry Andre, Qian Shi, Aimery De Gramont
Journal: Journal of Clinical Oncology (2023)

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P &lt; 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( P int =.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( P int =.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( P LRT &lt;.001). Conclusions: In pts with multiple sites mCRC, a statistically sig OS bnf of BEV added to CT was observed mainly among pts without lung mets. The overall effect of CT partner choice when combined with BEV can be different. In pts with single site, BEV did not seem to improve OS but the evaluation of efficacy of BEV in presence or absence lung mets was based on small number of pts and needs to be evaluated in trials with larger pts sample, especially trials including pts with single site lung mets. [Table: see text]
Natural history study and tissue procurement of neuroendocrine neoplasms (NENs).
Authors: Rosa Mallorson, Briana N. Cortez, Diana Grace Varghese, Amirkia Naimian, Tamika Magee, Sarah Kelley, Suresh Kumar, Nitin Roper, Yves Pommier, Jaydira Del Rivero
Journal: Journal of Clinical Oncology (2023)

TPS659 Background: Neuroendocrine neoplasms (NENs) are a rare spectrum of malignant neoplasms originating from neuroendocrine cells, most commonly affecting the gastrointestinal tract, pancreas, and lungs. Tumors may vary from low grade neuroendocrine tumors (NET) to high grade neuroendocrine carcinomas (NEC). The annual occurrence of NENs is increasing worldwide and currently the incidence in the US is about 6 cases per 100,000 people per year. A variety of therapeutic options are available for advanced NENs, however, when to apply a given option, what combination therapeutic approach should be used, how long treatment should be continued is unclear and controversial. Moreover, unlike common cancers, pre-clinical models for NENs are sorely limited. Without robust pre-clinical models our understanding of tumor pathophysiology and novel drug development can be challenging. Methods: A prospective study to evaluate the natural history and sample acquisition of NENs comprehensively and longitudinally. Patients ≥ 18 years old with histological confirmation of NENs, biochemical evidence of NENs, or by imaging studies of NENs are eligible. Participants are invited to NIH for biannual evaluations or as clinically indicated. Patients complete individual medical history, family history, and laboratory assessments including blood, saliva, and tumor for RNA/DNA analysis. A tumor analysis via a 500+ gene panel (Illumina TruSight Oncology 500 Panel) is performed for comprehensive genomic and epigenomic analysis. When feasible, fresh tissue is collected to develop pre-clinical models for drug testing. If clinically indicated, anatomic and functional imaging is performed. We aim to 1) create a repository of biological samples and conduct future investigations to understand the basic biology of NENs with the goal to develop novel treatment approaches, biomarkers of treatment response, and new prognostic and diagnostic models, 2) acquire clinical data so that the overall genomic, proteomic, and metabolomic alternations can be correlated to clinical parameters, 3) establish organoid cultures, cell line models, and xenograft models corresponding to NENs of various grades for drug screening. This protocol will evaluate the natural history of NENs, allow tissue acquisition, and study this heterogenous group of neoplasms with unique tumor biology, and current clinical management to stabilize correlations with clinical outcomes and develop novel therapies. Clinical trial information: NCT05237934 .
Outcomes of patients (pts) with metastatic colorectal cancer (mCRC) participating in phase I clinical trials: The Sarah Cannon Research Institute UK experience.
Authors: Ekaterina Ignatova, Elisa Fontana, Siyun Luo, Anja Williams, Hendrik-Tobias Arkenau
Journal: Journal of Clinical Oncology (2023)

142 Background: In the last decade immunotherapy, BRAF inhibitors (inh) and trifluridine-tipiracil became new standard of care (SoC) options for selected mCRC pts through the drug development pathway. In this study we aimed to evaluate clinical characteristics and outcomes of pts with mCRC participating in phase I trials. Methods: Electronic medical records from 10/2011 to 07/2022 were reviewed; pts who received at least one dose of trial drug were included. Data were analysed with descriptive statistic. Results: 81 (100%) pts were identified; 38 (47%) female; median age: 59 (range 31-80); 31 pts (38%) - right sided; 35 (44%) - RASmut, 29 (36%) - BRAFmut, 16 (20%) - RAS/BRAFw; MSI-H status was detected in 11 pts. Eleven pts participated in &gt;1 trial, for a total of 96 cases. Median follow-up was 7 months (m); overall response rate was 6.8%, mPFS: 2.9 m, mOS 18.8 m. Age&lt;50 (P=0,02), low lymphocyte/monocyte ratio (LMR ≤2.8) (P=0.02), in-situ primary tumour (P&lt;0.001), no adjuvant therapy (P=0,001), right sided tumour (P=0,02) were independently associated with shorter OS (univariate analysis); the last three variables remained significant in multivariate analysis. Outcomes according to 4 drug classes and others (chemotherapy-based +/- targeted agents) are shown. Conclusions: Phase 1 trials offer a reasonable therapeutic approach for pts with mCRC and early access to drugs with potential to become SoC in future. [Table: see text]
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis with 3-year follow-up.
Authors: Lin Shen, Yuxian Bai, Xiaoyan Lin, Wei Li, Jufeng Wang, Xiaochun Zhang, Hongming Pan, Chunmei Bai, Li Bai, Ying Cheng, Jingdong Zhang, Haijun Zhong, Yi Ba, Wenwei Hu, Rui-hua Xu, Weijian Guo, Shukui Qin, Rui Wang, Kendall Sullivan, Tianshu Liu
Journal: Journal of Clinical Oncology (2023)

353 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. Results from CheckMate 649 led to approval of 1L NIVO + chemo in multiple countries, including China. We report 3-year follow-up results in Chinese pts. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2-positive GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 37 month (mo) minimum follow-up, NIVO + chemo continued to demonstrate clinically meaningful improvement in OS and PFS vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts. The 36-mo OS rate was 31% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 26% vs 9% in all randomized pts, respectively. Objective response rate (ORR) (95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56-79) with NIVO + chemo and 48% (36-60) with chemo, and in all randomized patients was 66% (55-76) and 45% (35-56), respectively. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, with median duration of response (mDOR) (95% CI) of 12.5 mo (7.2-23.4) vs 6.9 mo (3.9-8.5); in all randomized pts, mDOR was 12.5 mo (7.2-17.7) vs 5.6 mo (4.4-8.3), respectively. No new safety signals were identified. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and durable objective responses vs chemo in Chinese pts, with an acceptable safety profile, consistent with the overall study population with advanced GC/GEJC/EAC. These results further support NIVO + chemo as a 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
A phase-Ib study of TRK-950 combined with anticancer treatment regimens in patients with gastric and gastro-esophageal junction (GEJ) cancer.
Authors: Philippe Alexandre Cassier, Marc Ryan Matrana, Diana L. Hanna, Ben George, Sunil Sharma, Ronan Joseph Kelly, Fumiyoshi Okano, Daniel D. Von Hoff, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2023)

361 Background: TRK-950 is a first-in-class humanized antibody raised against CAPRIN-1 which we have identified as a novel and universal target for cancer therapies. TRK-950 strongly and specifically binds to various cancer cells and shows anti-tumor effects via engagement of immune cells. A series of pre-clinical studies demonstrates its potency and safety. In the phase I study of TRK-950 monotherapy (NCT02990481), it appears safe and well tolerated. No DLT was observed and MTD was not reached at doses of 3-30mg/kg IV weekly. Here, we report on select cohort of the ongoing, multicenter phase Ib study of TRK-950 combined with standard of care (SOC) regimens in patients (pts) with gastric cancer including GEJ cancer (NCT03872947). Methods: Patients with gastric or gastro-esophageal junction (GEJ) cancer and measurable disease were enrolled in phase Ib study, and received paclitaxel on D1, 8, 15 and ramucirumab on D1, 15 of 28-day cycles. In addition TRK-950 was given 10 mg/kg IV weekly. DLT was evaluated during the first cycle. Response was assessed every 2 cycles up to Cycle 6 and every 3 cycles thereafter. Primary endpoint was safety and tolerability. Secondary endpoints included overall response rate (ORR), disease control rate (DCR) per REClST v1.1. Tumor CAPRIN-1 expression was retrospectively assessed by IHC. Results: Nine patients were enrolled, median age 58 yrs; Karnofsky performance status 80 (11%), 90 (67%), 100 (22%); 89% male, 11% female; median number of prior treatments 2 [1, 4]. TRK-950 in combination with ramucirumab and paclitaxel was well tolerated with no DLTs. Most common all-grade treatment-related AEs (TRAEs) were fatigue (67%), vomiting (33%), anemia (22%), nausea (22%), diarrhea (22%), neutrophil count decreased (22%) and decreased appetite (22%). Most common grade ≥ 3 TRAE in ≥ 20% of pts were anemia (22%) and neutrophil count decreased (22%). In 9 response-evaluable pts, ORR was 55.6% and DCR was 100%. Four patients had a screening CAPRIN-1 score of 3+, and all achieved partial response. Conclusions: TRK-950 binds to a newly described target, CAPRIN-1, and has an acceptable safety and tolerability profile when combined with ramucirumab and paclitaxel in gastric cancer including GEJ cancer. Preliminary clinical activity is demonstrated in pre-treated patients with encouraging response rates, particularly enriched by the expression of CAPRIN-1. Further antitumor activity is being confirmed by limiting patients to only 1 prior treatment regimen with an eye towards a randomized trial. Clinical trial information: NCT03872947 .